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The climate system responds to changes in the amount of atmospheric greenhouse gases or aerosols through rapid processes, triggered within hours and days, and through slower processes, where the full response may only be seen after centuries. In this paper, we aim to elucidate the mechanisms operating on time scales of hours to years to better understand the response of key climate quantities such as energy fluxes, temperature, and precipitation after a sudden increase in either carbon dioxide (CO2), black carbon (BC), or sulfate (SO4) aerosols. The results are based on idealized simulations from six global climate models. We find that the effect of changing ocean temperatures kicks in after a couple of months. Rapid precipitation reductions start occurring instantly and are established after just a few days. For BC, they constitute most of the equilibrium response. For CO2 and SO4, the magnitude of the precipitation response gradually increases as surface warming/cooling evolves, and for CO2, the sign of the response changes from negative to positive after 2 years. Rapid cloud adjustments are typically established within the first 24 h, and while the magnitude of cloud feedbacks for CO2 and SO4 increases over time, the geographical pattern of the equilibrium cloud change is present already after the first year. While there are model differences, our work underscores the overall similarity of the major time-varying processes and responses simulated by current global models and hence the robustness of key features of simulated responses to historical and future anthropogenic forcing. Significance Statement How does the climate system respond to a change in the amount of atmospheric greenhouse gases or aerosols? Some processes are rapid, responding within hours and days. Others are slow, and the full response to a forcing of the climate may only be seen after centuries. In this paper, we use six global climate models to investigate the time scales of climate responses to carbon dioxide, black carbon, and sulfate, focusing on key climate quantities, such as temperature, precipitation, and clouds. While there are ample model differences, our work underscores the overall similarity of the major time-varying processes and responses simulated by current global models and hence the robustness of key features of simulated responses to historical and future anthropogenic forcing.

A recurrent-neural-network-based deep-learning model was developed to estimate the three-axis joint angles of an entire body with 17 bones during walking from three inertial measurement units (IMUs) — one each on the left wrist and heels. In this model, the acceleration and angular velocity of the previous 49 frames and current frame were considered as inputs. The architecture comprises two hidden layers (two long short-term memory layers) and a dense layer. The performance of the model was evaluated using the National Institute of Advanced Industrial Science and Technology (AIST) Gait Database 2019 public dataset. Consequently, the root mean squared error of each joint angle was less than 12.28°. A comparison of the estimation results of the same model with IMUs at the pelvis and shanks revealed that the proposed model is advantageous in terms of balanced measurement accuracy and ease of use in realizing whole-body motion capture. Although the accuracy of the model was better than those of previous models in estimating the general whole-body motion from six IMUs, it was worse than that of a previous model in estimating only the lower-limb motion from three IMUs attached to the pelvis and shanks during walking. In the proposed model, IMUs are attached to the left wrist and heels, and whole-body motion can be easily captured using a smartwatch and smart shoes.

Removal of sulfide by gas stripping using biogas produced in an internal phase-separated reactor (IPSR) was evaluated during anaerobic treatment. The IPSR consisted of upper and lower segments with a gas–liquid partitioning (GLP) valve between the sections. Wastewater was fed to the upper segment in the first stage and then to the lower segment in the second stage. The GLP valve separated the liquid phase from the gaseous phase and supplied biogas from the lower segment to the upper segment. The IPSR and a control reactor were fed with synthetic wastewater and operated in parallel under an organic loading rate of 12 kg COD/(m3 day) at 35 °C. The sulfide concentration increased to 400–600 mg S/L, which is above the previously reported 50% inhibition level for methanogenic activity. The IPSR showed higher H2S removal performance than the control reactor and removed approximately twice the H2S as the control reactor at 400 mg S/L, indicating that it can be used for the stable treatment of wastewater containing high concentrations of sulfide.

A 46-year-old woman with lung cancer who received chemotherapy was admitted to our hospital for lower-lobe bilateral ground-glass opacity (GGO). GGO developed after the lung cancer diagnosis, deteriorated after the initiation of osimertinib, and incompletely decreased after interrupting osimertinib; therefore, flexible bronchoscopy was performed. Transbronchial lung biopsy histology and anti-granulocyte/macrophage colony-stimulating factor autoantibody positivity revealed autoimmune pulmonary alveolar proteinosis (aPAP) that did not require treatment. This rare case of aPAP comorbid with lung cancer suggested that using PAP findings to differentiate from drug-induced lung injury or lymphangitis is difficult and that osimertinib was suspected to exacerbate aPAP.

Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs.Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 μM was defined as heightened C-CS.Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 μM vs. 8.91 ± 5.5 μM, P 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD.Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.

Chloroplasts are a common feature of plant cells and aspects of their metabolism, including photosynthesis, are influenced by low-temperature conditions. Chloroplasts contain a small circular genome that encodes essential components of the photosynthetic apparatus and chloroplast transcription/translation machinery. Here, we show that in Arabidopsis, a nuclear-encoded sigma factor that controls chloroplast transcription (SIGMA FACTOR5) contributes to adaptation to low-temperature conditions. This process involves the regulation of SIGMA FACTOR5 expression in response to cold by the bZIP transcription factors ELONGATED HYPOCOTYL5 and ELONGATED HYPOCOTYL5 HOMOLOG. The response of this pathway to cold is gated by the circadian clock, and it enhances photosynthetic efficiency during long-term cold and freezing exposure. We identify a process that integrates low-temperature and circadian signals, and modulates the response of chloroplasts to low-temperature conditions.

Cefiderocol (CFDC) is a parenteral siderophore cephalosporin that is active against Gram-negative bacteria, including carbapenem-resistant isolates. We report the in vitro activity of CFDC and other antibiotics against 1,738 clinical isolates of Gram-negative bacilli (GNB) provided by five medical centers in five provinces of China in 2020 METHODS: : Antibiotic susceptibility testing was performed using the Clinical and Laboratory Standards Institute broth microdilution method.Against Pseudomonas aeruginosa and Acinetobacter spp., the CFDC concentration inhibiting the growth of 90% of the isolates (MICCFDC demonstrated potent in vitro activity against a recent collection of clinical isolates, including meropenem-non-susceptible isolates, obtained from medical centers in mainland China.

A 42-year-old Japanese woman was admitted for the evaluation of proteinuria. She had a history of four habitual abortions and valvular heart disease, including severe mitral regurgitation and moderate tricuspid regurgitation. A kidney biopsy showed fibrointimal thickening of interlobular arteries, fibrin thrombosis, and associated focal segmental sclerosis. Although the standard test for antiphospholipid (aPL) antibodies was negative, the patient was diagnosed with antiphospholipid syndrome (APS)-related disease by testing for phosphatidylserine dependent anti-prothrombin anticardiolipin antibody, a non-criterial aPL antibody. A kidney biopsy may lead to a diagnosis of APS in patients with negative laboratory test findings for APS.

The methods of spatial statistics have been successfully applied to the study of linguistic variation, especially for detecting the existence of spatial patterns in the geographical distribution of linguistic features. However, the use of local indicators of spatial autocorrelation for detecting spatial clusters have been limited to continuous variables, and we propose to apply the new method of Anselin and Li (2019) for categorical variables to linguistic data. We illustrate this method with the case of Japanese rendaku, or sequential voicing, whose dialectal variation is still poorly documented. Focusing on regional differences in the frequency of rendaku, we examined the occurrence of rendaku for four lexemes in 4,921 place names from all Japan. A statistical analysis of local spatial association and an unsupervised density-based cluster analysis revealed the existence of two cluster areas of high rendaku frequency centered around Wakayama and Fukushima-Yamagata prefectures. This suggests that rendaku is more frequent in those dialects, and we recommend that further studies in the dialectal variation of rendaku start by looking at those areas.

Objective Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model. Methods In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg/L (previously developed resistance on therapy), n = 3; 8 mg/L, n = 2; ≥32 mg/L, n = 10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol + ceftazidime/avibactam (C-CZA), cefiderocol + ampicillin/sulbactam (C-SAM) or cefiderocol + meropenem (C-MEM) HSRs. The mean change in log10 cfu/thigh compared with starting inoculum was assessed. Resistance development on treatment was a >4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking. Results Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA −3.75 ± 0.37 reduction in log10 cfu/thigh, C-SAM produced −3.55 ± 0.50 and C-MEM produced −2.18 ± 1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy. Conclusions Against cefiderocol-non-susceptible isolates, cefiderocol + ceftazidime/avibactam or ampicillin/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam against A. baumannii, including multi-drug-resistant isolates.

Background Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MICi). Methods Based on chequerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. Results The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT>MICi and analysed using the inhibitory effect sigmoid Imax model. fT>MICi calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT>MICi achieving growth inhibition, 1 log10 kill and 2 log10 kill, were 22, 38% and 75%, respectively. Conclusions The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae.

During last decade biomedical devices have become more and more performing, covering an increasing number of usages. In particular, subcutaneous devices represent one the most invasive yet innovative application; their battery management is one of the most challenging topics because, once implanted, they can be handled only through surgery, so wireless charge is the only way to feed subcutaneous systems with appreciable energy in a controlled manner. But differently from conventional consumer devices, in this scenario the energy delivered necessarily runs into human body and tissues, so the main challenge consists in maximizing the "energy delivered vs. energy dissipated in tissues" ratio, in order to guarantee human safety first while also conveying an appreciable amount of energy to the implanted device After analysing the state-of-the-art of the principal techniques, this paper proposes a novel architecture for low-power wireless charging, based on a Wiegand sensor used as a transducer in order to fulfill all the requirements from both electrical and medical points of view; such architecture is implemented inside an IC prototype in 0.35 μm lithography that acts as an ultra-low-power DC-DC buck converter and battery manager.

Cross-talk between peripheral neurons and immune cells is important in pain sensation. We identified Snx25 as a pain-modulating gene in a transgenic mouse line with reduced pain sensitivity. Conditional deletion of Snx25 in monocytes and macrophages, but not in peripheral sensory neurons, in mice (Snx25cKO mice) reduced pain responses in both normal and neuropathic conditions. Bone marrow transplantation using Snx25cKO and wild-type mice indicated that macrophages modulated pain sensitivity. Expression of sorting nexin (SNX)25 in dermal macrophages enhanced expression of the neurotrophic factor NGF through the inhibition of ubiquitin-mediated degradation of Nrf2, a transcription factor that activates transcription of Ngf. As such, dermal macrophages set the threshold for pain sensitivity through the production and secretion of NGF into the dermis, and they may cooperate with dorsal root ganglion macrophages in pain perception.

Introduction: The accuracy of serum immunoglobulin (Ig) G testing for diagnosis of stable bird-related fibrotic hypersensitivity pneumonitis (HP) is controversial. Furthermore, avian serum, extracts, or feathers were employed as antigens in bird-related HP; however, the usage of egg whites has not been reported. We investigated the utility of IgG testing against pigeon egg whites in patients with stable bird-related fibrotic HP. Methods: Patients having a positive inhalation test for pigeon antigen and a histological investigation with diagnostic confidence of fibrotic HP greater than moderate confidence were included. The control group consisted of patients with interstitial lung diseases (ILDs) other than HP. To select patients in the stable phase, patients with fibrotic HP were excluded if they were clinically considered to be in the acute exacerbation or acute phase. The IgG testing against pigeon egg whites by enzyme-linked immunosorbent assay and the commercialized anti-pigeon IgG testing by fluorescence enzyme immunoassay were investigated. Results: In this study, 37 patients with stable bird-related fibrotic HP and 32 patients with ILDs other than HP participated. Serum IgG testing for pigeon egg whites revealed that the control group’s optical density was 0.147 and the group with bird-related fibrotic HP had a mean value of 0.207 (p = 0.011). IgG testing in bronchial alveolar lavage fluid was not significantly higher in the bird-related fibrotic HP group than in controls (p = 0.42). No significant difference in area under the curve between an IgG testing against pigeon egg whites and a commercialized anti-pigeon IgG testing was observed (p = 0.24). Test accuracy for stable bird-related fibrotic HP ranged from 62% to 76% sensitivity and 59–66% specificity. Conclusion: IgG testing to identify the inciting antigen in patients with stable bird-related fibrotic HP had relatively low accuracy.

Drug-induced liver injury (DILI) is a major factor influencing new drug withdrawal; therefore, an appropriate toxicity assessment at the preclinical stage is required. Previous in silico models have been established using compound information listed in large data sources, thereby limiting the DILI risk prediction for new drugs. Herein, we first constructed a model to predict DILI risk based on a molecular initiating event (MIE) predicted by quantitative structure–activity relationships, admetSAR parameters (e.g. cytochrome P450 reactivity, plasma protein binding, and water-solubility), and clinical information (maximum daily dose [MDD] and reactive metabolite [RM]) for 186 compounds. The accuracy of the models using MIE, MDD, RM, and admetSAR alone were 43.2%, 47.3%, 77.0%, and 68.9%, while the “predicted MIE + admetSAR + MDD + RM” model’s accuracy was 75.7%. The contribution of MIE to the overall prediction accuracy was little effect or rather worsening it. However, it was considered that MIE was a valuable parameter and that it contributed to detect high DILI risk compounds in the early development stage. We next examined the effect of stepwise changes in MDD on altering the DILI risk and estimating the maximum safety dose (MSD) for clinical use based on structural information, admetSAR, and MIE parameters because it is important to estimate the dose that could prevent the DILI onset in clinical conditions. Low-MSD compounds might increase the DILI risk, as these compounds were classified as “most-DILI concern” at low doses. In conclusion, MIE parameters were especially useful to check the DILI concern compounds and to prevent the underestimation of DILI risk in the early stage of drug development.

A sensitive immunosensor is developed using membrane pores as the recognition site. A Cu-free click reaction is used to efficiently immobilize antibodies, and the sensor demonstrates rapid interleukin-6 detection in the picogram per milliliter range.